Three kinds of excipients were selected to investigate the anti-bitterness effect on the extremely bitter characteristics of Andrographis Herba decoction, and the optimal combined anti-bitterness formula was obtained. The preparation principle of different excipients was clarified by virtual screening and experimental verification to explore the advantages of the three kinds of excipients in the combined anti-bitterness effect. Sensory evaluation showed that mPEG_(2000)-PLLA_(2000), γ-cyclodextrin(γ-CD), and aspartame all had good anti-bitterness effect, which reduced the bitterness intensity of Andrographis Herba decoction by 0.5, 6, and 3 points, respectively. The anti-bitterness effect was superior when 0.15% mPEG_(2000)-PLLA_(2000), 1.60% γ-CD, and 0.04% aspartame were combined, and the taste score of the Andrographis Herba decoction decreased from 8 points(severe bitterness) to 1 point(almost no bitterness). Quantum chemistry calculations showed that mPEG_(2000)-PLLA_(2000) reduced the electrostatic potential of bitter groups, which spontaneously combined with it and formed a physical barrier, hindering the binding of bitter components to receptors. The interaction between γ-CD and bitter components was studied. It was found that the surface area and free energy of γ-CD decreased and the dipole moment increased, indicating that γ-CD included bitter components and self-assembled to form supramolecules. Molecular docking showed that hydroxy at position 14 and carbonyl at position 16 of andrographolide, and hydroxy at position 3 and 4, carbonyl at position 14, and five-membered lactone ring of dehydrated andrographolide were possibly the main bitter groups. The binding free energies of aspartame to bitter receptors TAS2 R10, TAS2 R14, and TAS2 R46 were-3.21,-1.55, and-2.52 kcal·mol~(-1), respectively, indicating that aspartame competed to inhibit the binding of bitter groups to bitter receptors. The results of content determination showed that the free amounts of andrographolide and dehydrated andrographolide in Andrographis Herba decoction were 0.23% and 0.28% respectively, while after adding flavor masking excipients, the dissociation amount of andrographolide and dehydrated andrographolide in the decoction decreased to 0.13% and 0.20%, respectively. The above results show that mPEG_(2000)-PLLA_(2000) involves some bitter components into it through micellar self-assembly to reconcile the entrance bitterness, and γ-CD includes the remaining bitter components in the real solution to control the main bitter taste. Aspartame further competes to inhibit the combination of bitter components and bitter receptors, and improves the taste to be sweet. Multi-excipients combined with anti-bitterness strategy significantly reduces the free concentration of bitter substances in Andrographis Herba decoction, and optimizes the taste of the decoction.
Andrographis ; Taste ; Aspartame ; Excipients ; Molecular Docking Simulation

Ochratoxin A is a natural contaminant of mouldy food and feed, which is produced by Penicillium and Aspergillus, and is suspected of being one of the etiological agents responsible for Balkan endemic nephropathy and the associated urinary tract tumors. For evaluation of the mutagenicity of ochratoxin A, we performed in vitro chromosome aberration tests using Chinese hamster lung fibroblast cells (CHL cells) and monkey kidney cells (VERO cells), in vivo micronueleus tests using ddY mouse bone marrow cells and somatic mutation and recombination tests (SMART) using Drosophila melanogaster. The results of chromosome aberration tests in CHL cells showed no incidence of increased structural and numerical aberrations regardless of metabolic activation, while in VERO cells treated with 2.0, 1.0, 0.5, 0.3 ug/ml of ochratoxin A showed significant increase of structural aberrations without metabolic activation. Aspartame and-phenylalanine, structural analogs of ochratoxin A, didn't affect the chromosome aberrations induced by ochratoxin A. The in vivo induction of micronucleated polychromatic erythrocytes were measured in bone marrows of ddY mice treated with 10.0, 5.0, 2.5mg/kg/10ml of ochratoxin A through intraperitoneal route once. At 24 and 48 hours after treatment, ochratoxin A didn't induce micronuclei in bone marrows of ddY mice. And at the concentration of 40, 20, 10 ug/ml of ochratoxin A, which was administered by feeding to larvae of Drosophila melanogaster, showed no incidence of increased multiple wing hairs and flares. Summarizing all results, we concluded that ochratoxin A is a kidney cell specific direct genotoxicant.
Animals ; Asian Continental Ancestry Group* ; Aspartame ; Aspergillus ; Balkan Nephropathy ; Biotransformation ; Bone Marrow ; Bone Marrow Cells ; Chromosome Aberrations ; Cricetinae ; Cricetulus* ; Drosophila melanogaster* ; Drosophila* ; Erythrocytes ; Fibroblasts ; Hair ; Haplorhini ; Humans ; Incidence ; Kidney ; Larva ; Lung* ; Mice* ; Penicillium ; Recombination, Genetic ; Urinary Tract ; Vero Cells*

Animals ; Aspartame ; pharmacology ; Carbon Tetrachloride ; administration & dosage ; Disease Models, Animal ; Ethanol ; administration & dosage ; chemistry ; Liver ; pathology ; ultrastructure ; Liver Cirrhosis, Experimental ; chemically induced ; pathology ; Male ; Plant Oils ; administration & dosage ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sweetening Agents ; pharmacology

BACKGROUND: Fever is a very common complication that has been related to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The incidence of acalculous cholecystitis is reportedly 0.5%–5% in critically ill patients, and cerebrovascular disease is a risk factor for acute cholecystitis (AC). However, abdominal evaluations are not typically performed for febrile patients who have recently undergone aSAH surgeries. In this study, we discuss our experiences with febrile aSAH patients who were eventually diagnosed with AC. METHODS: We retrospectively reviewed 192 consecutive patients who underwent aSAH from January 2009 to December 2012. We evaluated their characteristics, vital signs, laboratory findings, radiologic images, and pathological data from hospitalization. We defined fever as a body temperature of >38.3℃, according to the Society of Critical Care Medicine guidelines. We categorized the causes of fever and compared them between patients with and without AC. RESULTS: Of the 192 enrolled patients, two had a history of cholecystectomy, and eight (4.2%) were eventually diagnosed with AC. Among them, six patients had undergone laparoscopic cholecystectomy. In their pathological findings, two patients showed findings consistent with coexistent chronic cholecystitis, and two showed necrotic changes to the gall bladder. Patients with AC tended to have higher white blood cell counts, aspartame aminotransferase levels, and C-reactive protein levels than patients with fevers from other causes. Predictors of AC in the aSAH group were diabetes mellitus (odds ratio [OR], 8.758; P = 0.033) and the initial consecutive fasting time (OR, 1.325; P = 0.024). CONCLUSIONS: AC may cause fever in patients with aSAH. When patients with aSAH have a fever, diabetes mellitus and a long fasting time, AC should be suspected. A high degree of suspicion and a thorough abdominal examination of febrile aSAH patients allow for prompt diagnosis and treatment of this condition. Additionally, physicians should attempt to decrease the fasting time in aSAH patients.
Acalculous Cholecystitis ; Aneurysm* ; Aspartame ; Body Temperature ; C-Reactive Protein ; Cerebrovascular Disorders ; Cholecystectomy ; Cholecystectomy, Laparoscopic ; Cholecystitis ; Cholecystitis, Acute* ; Critical Care ; Critical Illness ; Diabetes Mellitus ; Diagnosis ; Fasting ; Fever* ; Hospitalization ; Humans ; Incidence ; Intensive Care Units ; Leukocyte Count ; Prognosis ; Retrospective Studies ; Risk Factors ; Subarachnoid Hemorrhage* ; Urinary Bladder ; Vital Signs

BACKGROUND: Fever is a very common complication that has been related to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The incidence of acalculous cholecystitis is reportedly 0.5%–5% in critically ill patients, and cerebrovascular disease is a risk factor for acute cholecystitis (AC). However, abdominal evaluations are not typically performed for febrile patients who have recently undergone aSAH surgeries. In this study, we discuss our experiences with febrile aSAH patients who were eventually diagnosed with AC. METHODS: We retrospectively reviewed 192 consecutive patients who underwent aSAH from January 2009 to December 2012. We evaluated their characteristics, vital signs, laboratory findings, radiologic images, and pathological data from hospitalization. We defined fever as a body temperature of >38.3℃, according to the Society of Critical Care Medicine guidelines. We categorized the causes of fever and compared them between patients with and without AC. RESULTS: Of the 192 enrolled patients, two had a history of cholecystectomy, and eight (4.2%) were eventually diagnosed with AC. Among them, six patients had undergone laparoscopic cholecystectomy. In their pathological findings, two patients showed findings consistent with coexistent chronic cholecystitis, and two showed necrotic changes to the gall bladder. Patients with AC tended to have higher white blood cell counts, aspartame aminotransferase levels, and C-reactive protein levels than patients with fevers from other causes. Predictors of AC in the aSAH group were diabetes mellitus (odds ratio [OR], 8.758; P = 0.033) and the initial consecutive fasting time (OR, 1.325; P = 0.024). CONCLUSIONS: AC may cause fever in patients with aSAH. When patients with aSAH have a fever, diabetes mellitus and a long fasting time, AC should be suspected. A high degree of suspicion and a thorough abdominal examination of febrile aSAH patients allow for prompt diagnosis and treatment of this condition. Additionally, physicians should attempt to decrease the fasting time in aSAH patients.
Acalculous Cholecystitis ; Aneurysm ; Aspartame ; Body Temperature ; C-Reactive Protein ; Cerebrovascular Disorders ; Cholecystectomy ; Cholecystectomy, Laparoscopic ; Cholecystitis ; Cholecystitis, Acute ; Critical Care ; Critical Illness ; Diabetes Mellitus ; Diagnosis ; Fasting ; Fever ; Hospitalization ; Humans ; Incidence ; Intensive Care Units ; Leukocyte Count ; Prognosis ; Retrospective Studies ; Risk Factors ; Subarachnoid Hemorrhage ; Urinary Bladder ; Vital Signs